The present invention relates to novel benzofuran derivatives potently binding to the 5-HT1A receptor, pharmaceutical compositions containing these compounds and the use thereof for the treatment of certain psychiatric and neurological disorders. Many of the compounds of the invention are also potent serotonin reuptake inhibitors and are considered to be particularly useful for the treatment of depression.
Clinical studies of known 5-HT1A partial agonists such as e.g. buspirone, ipsapirone and gepirone have shown that 5-HT1A partial agonists are useful in the treatment of anxiety disorders such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder (Glitz, D. A., Pohl, R., Drugs 1991, 41, 11). Preclinical studies indicate that full agonists also are useful in the treatment of the above mentioned anxiety related disorders (Schipper, Human Psychopharm., 1991, 6, S53).
There is also evidence, both clinical and preclinical, in support of a beneficial effect of 5-HT1A partial agonists in the treatment of depression as well as impulse control disorders and alcohol abuse (van Hest, Psychopharm., 1992, 107, 474; Schipper et al, Human Psychopharm., 1991, 6, S53; Cervo et al, Eur. J. Pharm., 1988, 158, 53; Glitz, D. A., Pohl, R., Drugs 1991, 41, 11; Grof et al., Int. Clin. Psychopharmacol. 1993, 8, 167-172; Ansseau et al., Human Psychopharmacol. 1993, 8, 279-283).
5-HT1A agonists and partial agonists inhibit isolation-induced aggression in male mice indicating that these compounds are useful in the treatment of aggression (Sanchxc3xa9z et al, Psychopharmacology, 1993, 110, 53-59).
Furthermore, 5-HT1A agonists have been reported to show activity in animal models predictive for antipsychotic effects (Wadenberg and Ahlenius, J. Neural. Transm., 1991, 83,43; Ahlenius, Pharmacol. and Toxicol., 1989, 64, 3; Lowe et al., J. Med. Chem., 1991, 34, 1860; New et al., J. Med. Chem., 1989, 32, 1147; and Martin et al., J. Med Chem., 1989, 32, 1052) and may therefore be useful in the treatment of psychotic disorders such as schizophrenia. Recent studies also indicate that 5-HT1A receptors are important in the serotonergic modulation of haloperidol-induced catalepsy (Hicks, Life Science 1990, 47, 1609) suggesting that 5-HT1A agonists are useful in the treatment of the side effects induced by conventional antipsychotic agents such as e.g. haloperidol.
5-HT1A agonists have shown neuroprotective properties in rodent models of focal and global cerebral ischaemia and may, therefore, be useful in the treatment of ischaemic disease states (Prehn , Eur. J. Pharm. 1991, 203, 213).
Pharmacological studies have been presented which indicate that 5-HT1A antagonists are useful in the treatment of senile dementia (Bowen et al., Trends Neur. Sci. 1992, 15, 84).
An overview of 5-HT1A antagonists and proposed potential therapeutic targets for these antagonists based upon preclinical and clinical data are presented by Schechter et al., Serotonin, 1997, Vol.2, Issue 7. It is stated that 5-HT1A antagonists may be useful in the treatment of schizophrenia, dementia associated with Alzheimer""s disease, and in combination with SSRI antidepressants also to be useful in the treatment of depression.
Both in animal models and in clinical trials it has been shown that 5-HT1A agonists exert antihypertensive effects via a central mechanism (Saxena and Villalxc3x3n, Trends Pharm. Sci. 1990, 11, 95; Gillis et al, J. Pharm. Exp. Ther. 1989, 248, 851). 5-HT1A ligands may, therefore, be beneficial in the treatment of cardiovascular disorders.
5-HT reuptake inhibitors are well known antidepressant drugs and useful for the treatment of panic disorders and social phobia
The effect of combined administration of a compound that inhibits serotonin reuptake and a 5HT1A receptor antagonist has been evaluated in several studies (Innis, R. B. et al., Eur. J. Pharmacol., 1987, 143, p 195-204 and Gartside, S. E., Br. J. Pharmacol. 1995, 115, p 1064-1070, Blier, P. et al, Trends Pharmacol. Sci. 1994, 15, 220). In these studies it was found that 5-HT1A receptor antagonists would abolish the initial brake on 5-HT neurotransmission induced by the serotonin reuptake inhibitors and thus produce an immediate boost of 5-HT transmission and a more rapid onset of therapeutic action.
Several patent applications have been filed which cover the use of a combination of a 5-HT1A antagonist and a serotonin reuptake inhibitor for the treatment of depression (see EP-A2-687 472 and EP-A-714 663).
Accordingly, agents acting on the 5-HT1A receptor, both agonists and antagonists, are believed to be of potential use in the therapy of psychiatric and neurological disorders and thus being highly desired. Furthermore, antagonists at the same time having potent serotonin reuptake inhibition activity may be useful for the treatment of depression.
It has now been found that compounds of a certain class of benzofuran derivatives bind to the 5-HT1A receptor with high affinities. Furthermore, it has been found that many of these compounds have potent serotonin reuptake inhibition activity.
Accordingly, the present invention relates to novel compounds of the general Formula I: 
wherein
R1 is hydrogen, halogen, trifluoromethyl, trifluoromethylsulfonyloxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C1-6 alkoxy, hydroxy, formyl, acyl, amino, C1-6 alkylamino, C2-12 dialkylamino, acylamino, C1-6 alkoxycarbonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, C2-12 dialkylaminocarbonylamino, nitro, cyano, COOH, or COOxe2x80x94C1-6 alkyl;
R2 and R3 are each independently selected from hydrogen, tifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl and C1-6 alkoxy;
n is 1, 2, 3, 4 or 5;
m is 0 or 1;
A is selected from the following groups: 
wherein
Z is O or S;
s is 0 or 1;
q is 0 or 1;
R4 is hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6alkynyl, C1-6alkyl-Aryl, or C1-6-alkyl-O-Aryl,
D is a spacer group selected from branched or straight chain C1-6-alkylene, C2-6-alkenylene and C2-6-alkynylene;
B is a group selected from a group of formula (II), (III), and (IV) 
wherein R5, R6, R7, R8, R9 and R10 are each independently selected among the R1 substituents;
or R8 and R9 together form a fused 5- or 6-membered ring optionally containing further heteroatoms;
or two of the groups of R5, R6 and R7 are linked together thereby forming a xe2x80x94oxe2x80x94(CH2)pxe2x80x94oxe2x80x94-bridge wherein p is 1 or 2;
Ar and Aryl are independently selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyrimidyl, 1-indolyl, 2-indolyl, 3-indolyl, indol-2-on-1-yl, indol-2-on-3-yl, 2- or 3-benzofuranyl, 2- or 3-benzothiophenyl, 1-naphthyl or 2-naphthyl, each optionally substituted with halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, hydroxy, C1-6 alkylsulfonyl, cyano, trifluoromethyl, trifluoromethylsulfonyloxy, C3-8 cycloalkyl, C3-8cycloalkyl-C1-6 alkyl, nitro, amino, C1-6 alkylamino, C2-12 dialkylamino, acylamino or alkylenedioxy;
its enantiomers, and pharmaceutically acceptable acid addition salt thereof.
In one embodiment of the invention A is a group of formula (1) and the other substituents are as defined above.
In another embodiment of the invention A is a group of formula (2) and the other substituents are as defined above.
In a third embodiment of the invention A is a group of formula (3) and the other substituents are as defined above.
In a fourth embodiment of the invention A is a group of formula (4) and the other substituents are as defined above.
Thus in a preferred embodiment of the invention A is a group of formula (1) and R4 is methyl, ethyl, propyl, prop-2-en-1-yl, 2-furylmethyl, or 2-phenoxyethyl; q=0; or A is a group of formula (1) and Z is O and the other substituents are as defined above.
In a further embodiment of the invention, B is a group of formula (II), preferably a alkoxysubstituted phenyl, a benzodioxan group or a 1,2-methylenedioxybenzene group and the other substituents are as defined above.
In a further embodiment of the invention, B is a group of formula (III), preferably a 3-indolyl group and the other substituents are as defined above.
In a further embodiment of the invention, B is a group of formula (HI), preferably a 3-indolyl group and the substituents R8 and R9 are preferably selected from hydrogen, methyl, fluoro, chloro, bromo, iodo, t-butyl or i-propyl in the 5-position; or fluoro, chloro or carboxy in the 7-position; or by 5,7-difluoro, 4-fluoro-7-methyl or 4-chloro-7-methyl; or the two substituents together form a pyridyl ring fused to the 3-indolyl.
In a further embodiment of the invention, B is a group of formula (IV) and the other substituents are as defined above.
Ar is preferably phenyl or phenyl substituted with halogen or CF3, most preferably substituted with F or Cl in the 4-position or Cl or CF3 in the 3-position.
R1 is preferably H, CN or F in the 5-position of the isobenzofuran group.
R2 and R3 are preferably selected from hydrogen or methyl.
n is preferably 2, 3 or 4.
m is preferably 0.
In a preferred embodiment of the invention n=2, 3 or 4; R2 and R3 are both hydrogen; R1 is H, CN or F in the 5-position of the isobenzofuran group; and Ar is phenyl which may be substituted with F or Cl in the 4-position or with Cl or CF3 in the 3-position and the other substituents are as defined above.
In another preferred embodiment of the invention, A is a group of formula (1); q=0; R4 is methyl; D is propylene; m=0; and B is a 1,4-benzodioxan group of Formula (II) attached in the 5-position and the other substituents are as defined above.
In another preferred embodiment of the invention, A is a group of formula (1); R4 is CH3 or prop-2-en-1-yl; n=3; D is ethylene or propylene; and B is a phenyl group wherein at least one substituent is OMe and the other substituents are as defined above.
In a further embodiment of the invention, A is a group of formula (1); q is 0; R4 is methyl, ethyl, propyl, 2-propen-1-yl, 2-furylmethyl or 2-phenoxyethyl; D is ethylene, propylene or butylene; m=0; and B is a 3-indolyl group of Formula (III) and the other substituents are as defined above.
In another preferred embodiment of the invention, A is a group of formula (2) or (3); n=3; m=0; and B is an 4- or 5-indolyl-group of Formula (IV) wherein R10 is hydrogen; R1 is CN in the 5-position of the isobenzofuran and Ar is 4-Fluorophenyl and the other substituents are as defined above.
The invention also relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or diluent.
In a further embodiment, the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of a disorder or disease responsive to the effect of 5-HT1A receptors.
In particular, the invention relates to the use of a compound according to the invention or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of depression, psychosis, anxiety disorders, panic disorder, obsessive compulsive disorder, impulse control disorder, alcohol abuse, aggression, ischaemia, senile dementia, cardiovascular disorders or social phobia.
In still another embodiment, the present invention relates to a method for the treatment of a disorder or disease of living animal body, including a human, which is responsive to the effect of 5-HT1A receptors comprising administering to such a living animal body, including a human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.
The compounds of the invention have high affinity for the 5-HT1A receptor. Accordingly, the compounds of the invention are considered useful for the treatment of depression, psychosis, anxiety disorders, such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder, impulse control disorder, alcohol abuse, aggression, ischaemia, senile dementia, cardiovascular disorders and social phobia.
Due to their combined antagonism of 5-HT1A receptors and serotonin reuptake inhibiting effect, many of the compounds of the invention are considered particularly useful as fast onset of action medicaments for the treatment of depression. The compounds may also be useful for the treatment of depression in patients who are resistant to treatment with currently available antidepressants.
Some of the compounds of general Formula I may exist as optical isomers thereof and such optical isomers are also embraced by the invention.
The term C1-6 alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl.
Similarly, C2-6 alkenyl and C2-6 alkynyl, respectively, designate such groups having from two to six carbon atoms, inclusive.
Halogen means fluoro, chloro, bromo, or iodo.
The term C3-8 cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The terms C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfonyl, designate such groups in which the alkyl group is C1-6 alkyl as defined above.
Acyl means xe2x80x94CO-alkyl wherein the alkyl group is C1-6 alkyl as defined above.
C1-6 alkylamino means xe2x80x94NH-alkyl, and C2-12 dialkylamino means xe2x80x94N-(alkyl)2 where the alkyl group is C1-6 alkyl as defined above.
Acylamino means xe2x80x94NH-acyl wherein acyl is as defined above.
C1-6 alkoxycarbonylamino means alkyl-Oxe2x80x94COxe2x80x94NHxe2x80x94 wherein the alkyl group is C1-6 alkyl as defined above.
C1-6 alkylaminocarbonylamino means alkyl-NHxe2x80x94COxe2x80x94NHxe2x80x94 wherein the alkyl group is C1-6 alkyl as defined above.
C2-12 dialkylaminocarbonylamino means (alkyl)2xe2x80x94Nxe2x80x94COxe2x80x94NHxe2x80x94 wherein the alkyl group is C1-6 alkyl as defined above.
Exemplary of organic acid addition salts according to the invention are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of inorganic acid addition salts according to the invention are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids. The acid addition salts of the invention are preferably pharmaceutically acceptable salts formed with non-toxic acids.
Furthermore, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
Some of the compounds of the present invention contain chiral centres and such compounds exist in the form of isomers (e.g. enantiomers). The invention includes all such isomers and any mixtures thereof including racemic mixtures.
Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallisation of d- or l- (tartrates, mandelates, or camphorsulphonate) salts for example. The compounds of the present invention may also be resolved by the formation of diastereomeric derivatives.
Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A. Collet, and S. Wilen in xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, New York (1981).
Optically active compounds can also be prepared from optically active starting materials.
The compounds of the invention can be prepared by one of the following methods comprising:
a) alkylating an amine of formula 
wherein R1, R2, R3, R4, n and Ar are as defined above with an alkylating agent of formula Gxe2x80x94(D)5xe2x80x94(Z)qxe2x80x94(CH2)mxe2x80x94B wherein D, Z, m, s, q and B are as defined above and G is a suitable leaving group such as halogen, mesylate, or tosylate;
b) alkylating an amine of formula Hxe2x80x94Axe2x80x94(CH2)mxe2x80x94B wherein A, m and B are as defined above with an alkylating agent of formula 
wherein R1, R2, R3, n and Ar are as defined above and G is a suitable leaving group such as halogen, mesylate, or tosylate;
c) reductive alkylation of an amine of formula 
wherein R1, R2, R3, R4, n and Ar are as defined above with an aldehyde of formula 
wherein Z, m, q and B are as defined above and t is 1-5;
d) reducing an amide of formula 
wherein R1, R2, R3, R4, n, q, Ar, Z, m and B are as defined above and t is 1-5;
e) releasing final product by the means of Hofmann elimination from a resin of formula 
wherein R1, R2, R3, R4, n, s, q, Ar, D, Z, m and B are as defined above, G is as defined above; and HORxe2x80x2 is a hydroxy substituted resin such as cross linked hydroxymethylpolystyrene or Wang resin.
f) reacting a compound of the formula 
wherein R1, R2, R3, R4, Ar, D and N are as defined above; (OH)2Q is a diol such as substituted ethylene glycol or propylene glycol, or a polymer bound diol, with a hydrazine of formula 
wherein R8 and R9 is as defined above, using Lewis acids as catalyst.
The alkylations according to Methods a and b are generally performed by boiling the reactants under reflux or by heating them at a fixed temperature in a suitable solvent such as acetone, methyl isobutyl ketone, tetrahydrofuran, dioxane, ethanol, 2-propanol, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide or 1-methyl-2-pyrrolidinone in the presence of a base such as triethylamine or potassium carbonate. Amines of formula V are prepared by means of demethylation according to the method described by Bigler et al, Eur. J. Med. Chem. Chim. Ther, 1977, 12, 289-295, or by the methods outlined in examples 14 and 15. The starting materials used in example 14 were prepared as described in example 9 or from readily available compounds by standard methods. The enantiomers of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile used as starting material for the demethylation are prepared as described in EP patent No. 347066. The alkylating agents of formula Gxe2x80x94(D)sxe2x80x94(Zqxe2x80x94(CH2)mxe2x80x94B are commercially available, prepared by methods obvious to the chemist skilled in the art or prepared as exemplified in Examples 5-8. Ethyl 1,4-benzodioxan-5-carboxylate used as starting material in Example 5 is prepared by methods obvious to the chemist skilled in the art from the corresponding carboxylic acid prepared according to literature (Fuson et al., J. Org. Chem., 1948, 13, 489). Alkylating agents of formula VI are prepared from the corresponding dimethylamine (Formula VI: G=N(Me)2) as exemplified in example 9. The secondary amines of formula Hxe2x80x94Axe2x80x94(CH2)mxe2x80x94B are commercially available, prepared by methods obvious to the chemist skilled in the art or prepared according to literature procedures. 1-(2-methoxyphenyl)piperazine is prepared according to Pollard et al., J. Org. Chem., 1958, 23, 1333. [2-(2-Methoxyphenoxy)ethyl]methylamine and [2-(3-methoxyphenoxy)ethyl]-methylamine are prepared as exemplified in Examples 7 and 10 using commercially available 2-methoxyphenoxyacetic acid and 3-methoxyphenoxyacetic acid, respectively, as starting materials.
The reductive alkylations according to method c and d are performed according to standard literature methods using NaCNBH3, NaBH4 or NaBH(OAc)3 as reducing agent in a suitable solvent.
The reductions according to Methods e and f are generally performed by use of LiAlH4, AlH3 or diborane in an inert solvent such as tetrahydrofuran, dioxane, or diethyl ether at room temperature or at a slightly elevated temperature.
The release of final products by means of Hofmann elimination in Method g is generally performed by the use of an organic base such as triethylamine or diisopropylethylamine in an aprotic organic solvent such as dichloromethane, toluene or N,N-dimethylformamide. The polymer of formula XII is prepared in a synthesis sequence as exemplified in Example 4 and described in the following. The starting acryl ester resin (CH2CHC(O)ORxe2x80x2) is prepared according to literature procedures (Brown et al., J. Am. Chem. Soc., 1997, 119, 3288-95) by acylation of commercially available hydroxy substituted resins such as cross linked hydroxymethylpolystyrene or Wang resin with acryloyl chloride. Secondary amines of formula H2Nxe2x80x94Dxe2x80x94Zxe2x80x94(CH2)mxe2x80x94B are introduced by Michael addition in an organic solvent such as N,N-dimethylformamide at ambient temperature. The secondary amines used are either commercially available, prepared by methods obvious to the chemist skilled in the art or prepared according to literature procedures. 3-(2-Methoxyphenyl)propylamine is prepared according to Leeson et al., J. Med. Chem. 1988, 31, 37-54, 3-(3-methoxyphenyl)propylamine according to Meise et al. Liebigs Ann. Chem., 1987, 639-42, 3-(2-methoxyphenoxy)propylamine according to Augsein et al., J. Med. Chem., 1965, 8, 356-67, 3-(3-methoxyphenoxy)propylamine according to Brenner et al., Aust. J. Chem. 1984, 37, 129-41, 2-benzyloxyethylamine according to Harder et al. Chem. Ber. 1964, 97, 510-19, 2-(1H-indolyl-3-yl)ethylamine according to Nenitzescu et al., Chem. Ber., 1958, 91, 1141-45 and 3-(1H-indolyl-3-yl)propylamine according to Jackson et al., J. Am. Chem. Soc., 1930, 52, 5029. The second diversifying group is introduced by means of alkylation with an agent of formula VI by boiling the reactants under reflux or by heating them at a fixed temperature in a suitable solvent such as tetrahydrofuran, dioxane, ethanol, 2-propanol, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide or 1-methyl-2-pyrrolidinone in the presence of a soluble base such as diisopropylethylamine or triethylamine, or by means of reductive alkylation with an aldehyde of formula IX using standard solid phase synthesis literature methods using NaCNBH3, NaBH4 or NaBH(OAc)3 as reducing agent in a suitable solvent. The third diversifying group was introduced by means of quarternisation using an alkylating agent of formula R4-G in an organic solvent such as tetrahydrofuran, dioxane, ethanol, 2-propanol, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide or 1-methyl-2-pyrrolidinone at ambient temperature giving resins of formula XII.
The indole formation according to method h is performed by the reaction of acetals of formula XIII with aryl hydrazines of formula XIV resulting in the corresponding hydrazones, which subsequently are converted into indoles by means of the Fischer indole synthesis. The synthesis sequence is preferably performed as a one-pot procedure using a Lewis acid catalysts, preferably zinc chloride or boron fluoride, or protic acids, preferably sulfuric acid or phosphoric acid, in a suitable solvent such as acetic acid or ethanol at an elevated temperature. Acetals of formula XIII are prepared by alkylation of secondary amines of formula V with acetals of formula XV 
using the conditions described above for methods a and b. Alternatively, the acetals of formula XIII are prepared by alkylation of acetals of formula XVI 
with an alkylating agent of formula VI using the conditions described above for methods a and b. The acetals of formula XVI are prepared by reaction of acetals of formula XV with primary amines of formula NH2R4 using standard conditions.
Polymer bound acetals of formula XV is prepared by reaction of aldehydes of formula Gxe2x80x94Bxe2x80x94CH2CHO with commercially available 2,2-dimethyl-1,3dioxolan4-yl-methoxymethyl polystyrene in a suitable solvent such as toluene, using p-toluenesulfonic acid as catalyst at elevated temperature. 4-Chlorobutanal, 5-chloropentanal, and 6-chlorohexanal were prepared in analogy to the method described by Normant et al., Tetrahedron 1994, 50 (40), 11665.